Process of preparing 5-amino-5,6,7,8-tetrahydroquinolines and related compounds

ABSTRACT

Novel 5-amino-5,6,7,8-tetrahydroquinolines and related compounds, intermediates and processes for the preparation thereof, and methods for relieving memory dysfunction utilizing compounds or compositions thereof are disclosed.

This is a division of application Ser. No. 07/833,484 filed Feb. 10,1992, now U.S. Pat. No. 5,216,164 which is a division of applicationSer. No. 07/620,811 filed Dec. 3, 1990, now U.S. Pat. No. 5,110,815.

The present invention relates to tetrahydroquinolines and relatedcompounds. More particularly, the present invention relates to5-amino-5,6,7,8-tetrahydroquinolines of the formula ##STR1## wherein X-Yis a group of the formula ##STR2## wherein R is hydrogen, alkyl,alkenyl, alkynyl, or arylalkyl, or a group of the formula ##STR3##wherein R¹ is hydrogen, alkyl or arylalkyl; R² and R³ are independentlyhydrogen, alkyl, arylalkyl, diarylalkyl, cycloalkenylalkyl, alkoxy,arylalkoxy, or alkanoyl; R² and R³ taken together with the nitrogen atomto which they are attached form a group of the formula ##STR4## whereinp is 0 or 1, a group of the formula ##STR5## wherein Z is O, S, or agroup of the formula NR⁶ wherein R⁶ is hydrogen, alkyl, or arylalkyl; R⁴is hydrogen, alkyl or arylalkyl; R⁵ is hydrogen, alkyl or arylalkyl; andm is 0, 1, or 2, and n is 1 or 2; or geometrical and optical isomersthereof, or a pharmaceutically acceptable salt thereof, which are usefulfor relieving memory dysfunction, for example, memory dysfunction suchas that associated with reduced cholinergic function in Alzheimer'sdisease alone or in combination with adjuvants.

Subgeneric to the 5-amino-5,6,7,8-tetrahydroquinolines of the presentinvention are compounds wherein:

a. X-Y is a group of the formula ##STR6## and m is 1; and

b. X-Y is a group of the formula ##STR7## and m is 1.

The present invention also relates to5-hydroxy-5,6,7,8-tetrahydroisoquinolines of the formula ##STR8##wherein X-Y is a group of the formula ##STR9## wherein R is hydrogen,alkyl, alkenyl, alkynyl, or arylalkyl, or a group of the formula##STR10## wherein R¹ is alkyl or arylalkyl; R⁴ is hydrogen, alkyl, orarylalkyl; R⁵ is hydrogen, alkyl, or arylalkyl; and m is 0, 1, or 2; andn is 1 or 2; or the geometric or optical isomers thereof, which areuseful as intermediates for the preparation of the present5-amino-5,6,7,8-tetrahydroquinolines.

As used throughout the specification and appended claims, the term"alkyl" shall mean a straight or branched chain hydrocarbon groupcontaining no unsaturation and having from 1 to 8 carbon atoms. Examplesof alkyl groups are methyl, ethyl, propyl, isopropyl, neopentyl,tert-pentyl, hexyl, pentyl, and octyl, and the like. The term "alkenyl"shall mean a straight or branched chain hydrocarbon group containing onecarbon to carbon double bond and having 3 to 8 carbon atoms. Examples ofalkenyl groups are propenyl, butenyl, pentenyl, hexenyl, heptenyl,octenyl, and the like. The term "alkynyl" refers to a straight orbranched chain hydrocarbon radical containing unsaturation in the formof a single carbon to carbon triple bond and having from 3 to 7 carbonatoms such as 2-propynyl, 2-butynyl, 1-methyl-2-butynyl,4-methyl-2-pentynyl, 4,4-dimethyl-2-butynyl and the like. The term"cycloalkenyl" refers to a hydrocarbon group having one carbocyclic ringof 4 to 6 carbon atoms and one carbon-to-carbon double bond. Examples ofcycloalkenyl groups are cyclobutenyl, cyclopentenyl, and cyclohexenyl.The term "aryl" shall mean phenyl or phenyl substituted by one or morechloro, bromo, fluoro, methoxy, alkyl of from 1 to 8 carbon atoms,nitro, hydroxy, or trifluoromethyl groups. The term "aralkyl" refers toa radical formed by attachment of an alkyl function to an aryl moiety.The term "alkanol" refers to a compound formed by a combination of analkyl group and a hydroxy radical. Examples of alkanols are methanol,ethanol, 1- and 2-propanol, 1,2-dimethylethanol, hexanol, octanol andthe like. The term "alkanoic acid" refers to a compound formed bycombination of a carboxyl group with a hydrogen atom or alkyl group.Examples of alkanoic acids are formic acid, acetic acid, propanoic acid,2,2-dimethylacetic acid, hexanoic acid, octanoic acid and the like. Theterm "halogen" refers to a member of the family consisting of fluorine,chlorine, bromine or iodine. The term "alkanoyl" refers to the radicalformed by removal of the hydroxyl function from an alkanoic acid.Examples of alkanoyl groups are formyl, acetyl, propionyl,2,2-dimethylacetyl, hexanoyl, octanoyl and the like. The term "alkoxy"refers to a monovalent substituent which consists of an alkyl grouplinked through an ether oxygen and having its free valence bond from theether oxygen such as methoxy, ethoxy, propoxy, butoxy,1,1-dimethylethoxy, pentoxy, 3-methylpentoxy, 2-ethylpentoxy, octoxy.The term "lower" as applied to any of the aforementioned groups shallmean a group having a carbon skeleton containing up to and including 6carbon atoms.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipodes may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diastereomeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein and the formulasof the compounds shown herein are intended to encompass all possibleoptical isomers of the compounds so depicted.

The novel 5-amino-5,6,7,8-tetrahydroquinolines and related compounds ofthe present invention are synthesized by the processes illustrated inReaction Schemes A and B. The following discussion focuses on thetetrahydroquinoline series. The processes shown in the Reaction Schemesmay be applied to the synthesis of the related compounds.

To gain entry into the primary amino-5,6,7,8-tetrahydroquinoline system1a/1b, i.e., to prepare a tautomeric2-hydroxy-5,6,7,8-tetrahydroquinoline1a/5,6,7,8-tetrahydro-2(1H)-quinolinone 1b, characterized by thepresence of a primary amino group (NH₂), a5-oxo-5,6,7,8-tetrahydro-2(1H)-quinolinone 2 (shown as one tautomer),the preparation of which is described in L. Mosti, et al., Journal ofHeterocyclic Chemistry, 22, 1503 (1985), is O-alkylated to a2-alkoxy-(or -arylalkoxy)-5-oxo-5,6,7,8-tetrahydroquinoline 3, which isconverted to a 2-alkoxy-(or-aryloxy)-5-hydroxy-5,6,7,8-tetrahydroquinoline 4 and aminated to a5-alkanoylamino-2-alkoxy-(or arylalkoxy)-5,6,7,8-tetrahydroquinoline 5.In turn, a 5-alkanoylamino-2-alkoxy-(orarylalkoxy)-5,6,7,8-tetrahydroquinoline 5 is cleaved to a5-alkanoylamino-2-hydroxy-5,6,7,8-tetrahydroquinoline6a/5-alkanoylamino-5,6,7,8-tetrahydro-2(1H)-quinolinone 6b andhydrolyzed to a primary aminoquinoline 1a/1b.

The O-alkylation is conveniently performed by treating a2(1H)-quinolinone 2 with a halide of formula 11 ##STR11## wherein R¹ isalkyl or arylalkyl and Hal is halogen in an aromatic solvent such as,for example, benzene, toluene, xylene, mesitylene, and the like, in thepresence of a base such as sodium carbonate, potassium carbonate, orsilver carbonate. Toluene and silver carbonate are preferred. Thealkylation proceeds readily at about ambient temperature (about 25° C.).Reduced temperatures (about 0° to about 25° C.) and elevatedtemperatures (about 25° to about 50° C.) may be employed, however.

The conversion of a 5-oxoquinoline 3 to a 5-hydroxyquinoline 4 whereinR⁴ is alkyl or arylalkyl is effected by the Grignard technique. Thus,treatment of a 5-oxoquinoline 3 with a Grignard reagent of formula 12##STR12## wherein R⁴ is alkyl or arylalkyl and Hal is as above in anaromatic solvent (e.g., benzene, toluene, xylene, or mesitylene) or anethereal solvent (e.g., diethyl ether, 2-methoxyethyl ether,tetrahydrofuran, and dioxan) at a reaction temperature of from about 0°to about 50° C. provides a 5-hydroxyquinoline 4 wherein R⁴ is as above.An aromatic solvent is preferred; toluene is most preferred. Thepreferred reaction temperature is about 25° C. A 5-hydroxyquinoline 4wherein R⁴ is hydrogen may be prepared by reduction of a 5-oxoquinoline4 with, for example, an alkali metal borohydride such as sodiumborohydride or potassium borohydride in an alkanol such as ethanol or2-propanol under conventional conditions.

The amination of a 5-hydroxy-5,6,7,8-tetrahydroquinoline 4 to a5-alkanoylamino-5,6,7,8-tetrahydroquinoline 5 is accomplished bytreating a carbinol 4 with a nitrile of formula 13 ##STR13## wherein R⁷is alkyl in the presence of a strong acid. Included among strong acidsare mineral acids, e.g., hydrochloride acid, hydrobromic acid, andsulfuric acid, and organic acids, e.g., sulfonic acids such asbenzenesulfonic acid and para-toluenesulfonic acid, and carboxylic acidssuch as trifluoroacetic acid. Mineral acids are preferred; sulfuric acidis most preferred. The amination is generally performed in excessreactant 13, the nitrile acting both as the aminating agent and solvent.The reaction temperature is not narrowly critical and proceeds at aconvenient rate at about 25° C. (ambient temperature). ReducedTemperatures within the range from about 0° to about 25° C. and elevatedtemperatures within the range from about 25° to about 50° C. may beemployed, depending upon the specific reactants.

The cleavage of a 2-arylalkoxy-5,6,7,8-tetrahydroquinoline 5 wherein R¹is phenylmethyl or substituted phenylmethyl to a2-hydroxy-5,6,7,8-tetrahydroquinoline6a/5,6,7,8-tetrahydro-2(1H)-quinolinone 6b is carried out at about 25°C., under hydrogenolysis conditions in an alkanol such as methanol,ethanol, or 1- or 2-propanol, ethanol being preferred, in the presenceof a noble metal catalyst, supported or unsupported, such aspalladium-on-carbon, platinum, rhodium-on-alumina, or ruthenium, 10%palladium-on-carbon, being preferred, under hydrogen pressure within therange of about 25 to about 85 pounds per square inch (psi), about 55 psiof hydrogen being preferred. The hydrolysis of a5-alkanoylamino-5,6,7,8-tetrahydroquinoline6a/5-alkanoylamino-5,6,7,8-tetrahydro-2(1H)-quinolinone 6b to theultimate primary 5-aminoquinoline 1a/5-amino-2(1H)-quinolinone 1b may beachieved by conventional basic hydrolysis (e.g., sodium hydroxide orpotassium hydroxide in methanol or ethanol) or acidic hydrolysis (e.g.,hydrochloric acid or sulfuric acid in ethanol or 2-propanol) methods.

Alternatively, a tautomeric primary amino-5,6,7,8-tetrahydroquinoline1a/1b is prepared by condensing a 5,6,7,8-tetrahydroquinolinol 4 with analkoxyamine of formula 14 ##STR14## wherein R⁸ is phenyl or phenylsubstituted by one or more halogen, alkoxy, alkyl, or trifluoromethylgroups to yield a methoxyamino-5,6,7,8-tetrahydroquinoline 7 which isfirst cleaved to a 5,6,7,8-tetrahydroquinolinamine 8 and then to atautomeric aminoquinoline 1a/1b. The condensation, an amination, isachieved by contacting a tetrahydroquinolinol 4 with a methoxyamine 14,in the presence of a strong mineral or organic acid in an aromaticsolvent. Included among strong mineral acids are hydrohalic acids, forexample, hydrochloric acid, hydrobromic acid, and the like, and sulfuricacid, nitric acid, and phosphoric acid. Included among strong organicacids are dihaloalkanoic acids, for example, dichloroacetic acid,trihaloalkanoic acids, for example, trifluoroacetic acid, andarylsulfonic acids, for example, phenylsulfonic acid, 4-tolylsulfonicacid, 2-naphthalenesulfonic acid, and the like. Included among aromaticsolvents are benzene, toluene, xylene, and mesitylene. Trifluoroaceticacid and toluene are the preferred strong acid and aromatic solvent. Theamination is generally conducted at about 25° C. Higher (from about 25°C. to the boiling point of the reaction mixture) and lower (from about0° C. to about 25° C.) may be employed. An amination temperature ofabout 25° C. is preferred.

The first cleavage, i.e., the cleavage of the methoxyamino function of 7to provide the primary amino function of 8 is accomplished in anethereal solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane,2-methoxyethyl ether, and diethyl ether by means of a borane complex,for example, borane tetrahydrofuran complex. Elevated cleavagetemperatures of about 50° C. to about the reflux temperature arepreferred.

The second cleavage reaction, namely, the hydrogenolyis of the benzylether function of 8 to afford a tautomeric aminoquinoline 1a/1b iseffected by the processes described above for the cleavage of a2-arylalkoxyquinoline 5 to a tautomer 6a/6b.

A 1-alkyl-, 1-alkenyl- or1-arylalkyl-5-amino-5,6,7,8-tetrahydro-2(1H)-quinolinone 10 isconstructed by alkylating a tautomeric 5-aminoquinoline 1a/1b with ahalide of formula 15. ##STR15## wherein R⁹ is alkyl, alkenyl, orarylalkyl and Hal is as before. The alkylation is performed by firstabstracting a proton from the tautomer 1a/1b with, for example, analkali metal hydride in an aprotic dipolar solvent, and treating theanion, so formed, with a halide 15. Suitable alkali metal hydridesinclude lithium hydride, sodium hydride, and potassium hydride. Suitableaprotic dipolar solvents include dimethylacetamide, dimethylformamide,dimethylsulfoxide, and hexamethylphosphoramide. An alkylation employingan alkyl, alkenyl-, or arylalkyl iodide, i.e., a halide 15 wherein Halis iodo, and sodium hydride in dimethylformamide is preferred. Thealkylation of tautomer 1a/1b to a 1-substituted derivative 10 proceedsreadily at about 25° C. Elevated temperatures within the range of about25° to about 50° C. and reduced temperatures within the range of about5° to about 25° C. may be employed to effect the desired transformation.

To gain entry into the secondary amino-5,6,7,8-tetrahydroquinolinesystem 17a/17b, i.e., to prepare a tautomeric2-hydroxy-5,6,7,8-tetrahydroquinoline17a/5,6,7,8-tetrahydro-2(1H)-quinolinone 17b, characterized by thepresence of a secondary amino group (NHR²), anarylmethoxy-5,6,7,8-tetrahydroquinolinamine 7 is alkylated to anN-alkyl-, (-or N-arylalkyl)-N-arylmethoxy-5,6,7,8-tetra-hydroquinolinamine 9, which is first cleavedat the amino function to give an N-alkyl-, (orN-arylalkyl)-5,6,7,8-tetrahydroquinolinamine 16 and then at the oxygenfunction to yield a tautomeric 5,6,7,8-tetrahydroquinoline 17a/17b. Thealkylation of an alkoxyamine 7 to an N-alkylalkoxyamine 9 is carried outby forming the amino anion with an organometallic, for example, analkylalkali metal such as methyllithium or an arylalkali metal such asphenylithium in an ethereal solvent such as diethyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, 2-methoxyethyl ether, orcombinations thereof, and treating the anion, so formed, with a halide15. The anion formation is preferably carried out at a reducedtemperature of about -78° C., while the alkylation of the anion ispreferably performed at about 25° C.

The cleavages of the N-arylmethoxy group of 9 and the O-arylalkyl groupof 16 are achieved by processes substantially similar to those utilizedfor the conversions of 7 to 8 and 5 to 6a/6b, described above.

In an alternative approach to a secondaryamino-5,6,7,8-tetrahydroquinolinone 21 and a tautomeric5,6,7,8-tetrahydroquinolinone/5,6,7,8,-tetrahydroquinoline 25a/25b, a1-alkyl-5-oxo-5,6,7,8-tetrahydro-2(1H)-quinolinone 19, preparedaccording to the procedures outlined in R. Albrecht and E. Schroder,Arch. Pharmaz., 308, 588 (1975), is condensed with a primary amine offormula 22. ##STR16## wherein R² is alkyl or arylalkyl and R³ ishydrogen to provide an intermediate imine of formula 20 wherein the bond(--) is between the C-5 carbon atom and the amino nitrogen which isreduced to a secondary 5-alkyl- or5-arylalkylamino-5,6,7,8-tetrahydro-2(1H)-quinolinone 21. Thecondensation, providing an intermediate imine 20, is conducted in thepresence of a strong carboxylic or sulfonic acid such as, for example,trifluoroacetic acid, or benzenesulfonic or para-toluenesulfonic acid inan aromatic solvent such as, for example, benzene or toluene, optionallywith azeotropic removal of the water formed in the reaction. While theamount of strong acid used to promote the condensation is not critical,catalytic amounts are preferred. para-Toluenesulfonic acid and tolueneare the preferred strong acid and aromatic solvent.

The intermediate imine 20 is also prepared by condensing a1-alkyl-5-oxo-5,6,7,8-tetrahydro-2(1H)-quinolinone 19 with primary amine22 in the presence of titanium tetra-isopropoxide in a suitable solvent,for example, acetonitrile at a non-critical condensation temperature ofabout ambient temperature.

The reduction of the intermediate imine 20, generally conducted withoutpurification, is effected by, for example, an alkali metal borohydridesuch as lithium borohydride, sodium borohydride, or potassiumborohydride in an alkanol such as methanol, ethanol, or 1- or 2-propanolat about 0° to about 50° C. The preferred reduction conditions aresodium borohydride in ethanol at about 25° C.

Similarly, a tautomeric5,6,7,8-tetrahydroquinolinone/5,6,7,8-tetrahydroquinoline 25a/25b isprepared by condensing a 2-aryalkyl-5-oxo-5,6,7,8-tetrahydroquinoline 23wherein R is aryalkyl and R⁵ and m are as before with a primary amine 22to provide an imine 24 which is reduced and cleaved to a tautomeric5-aminoquinoline 25a/25b, the process steps being performed byprocedures substantially the same as those, for example, describedhereinbefore for the respective conversions of 19 to 20 and 16 to17a/17b.

By employing a secondary amine, i.e., an amine of formula 22 whereinneither R² or R³ is hydrogen, and the procedures hereindescribed for theconversion of 19 to 21 and 23 to 25a/25b, one may construct a5-(tertiary)-amino-5,6,7,8-tetrahydro-2(1H)-quinolinone 21 or atautomeric 5-(tertiary)-amino-5,6,7,8-tetrahydroquinoline25a/-quinolinone 25b.

By employing a aryloxyamine, i.e., a aryloxyamine of formula 22 whereinR² is hydrogen and R³ is arylalkoxy and the processes for the conversionof 23 to 25a/25b, one can prepare anN-arylalkoxy-5,6,7,8-tetrahydroquinoline 27 wherein R⁸ is arylalkyl viathe intermediate oxime 26, which may be cleaved to a tautomeric primaryamino-5,6,7,8-tetrahydroquinoline 25a/tetrahydroquinolinone 25b. In thisapproach, an O-arylakylhydroxylamine is used in the form of itshydrohalide such as a hydrochloride in an alkanol such as ethanol in thepresence of a weak base such as an alkali metal acetate, e.g., sodiumacetate, at an elevated temperature of about the reflux temperature ofthe reaction medium, and the reduction is performed by an alkali metalcyanoborohydride such as sodium cyanoborohydride in an alkanoic acidsuch as acetic acid at a temperature of about 25° C. The cleavage of anO,N-diarylalkoxy-5,6,7,8-tetrahydroquinoline 27 to a tautomericquinoline/quinolinone 25a/25b may be accomplished by following thedirections for the cleavage of 7 to 8 and 8 to 1a/1b.

Still another approach to 5-amino-5,6,7,8-tetrahydroquinolines andrelated compounds involves acylation of aN,2-bis(arylalkoxy)-5,6,7,8-tetrahydro-5-quinolinamine 27 to an amide 28which may be converted, for example, to a tautomeric quinolinol1a/quinolinone 1b by processes hereinbeforedescribed. The acylation isaccomplished by treating a 5-quinolinamine 27 with an alkanoic acidanhydride of formula 29 ##STR17## in a halocarbon solvent such asdichloromethane or trichloroethane, dichloromethane being preferred, inthe presence of a promoter such as a N,N-dialkylaminopyridine, forexample, N,N-dimethylpyridine at a reaction temperature of from about 0°to 50° C., a reaction temperature of about 25° C. being preferred.

In addition to the procedures outlined in R. Albrecht and E. Schroder,Arch. Pharmaz., 308, 588 (1975) for the transformation of anN-unsubstituted quinolone 18 to a N-substituted, i.e., an N-alkyl,-alkenyl, or -phenylmethylquinolone 19, the conversion of 18 to 19 isperformed by treating a quinolone 18 with a halide of formula 30##STR18## wherein R is alkyl, alkenyl, or phenylmethyl in an aproticdipolar solvent such as dimethylacetamide, dimethylformamide,hexamethylphosphoramide, or dimethylsulfoxide in the presence of analkali metal hydride such as lithium hydride, potassium hydride orsodium hydride at a condensation temperature of about 0° C. to about 50°C. The preferred reaction conditions are lithium hydride indimethylformamide at a temperature of about 25° C.

Substituents on the 5-amino-5,6,7,8-tetrahydroquinolines of the presentinvention may be modified by conventional methods. For example, analkenyl group of aminoquinolinone 21 wherein R is alkenyl is reduced byhydrogen in the presence of palladium-on-carbon in ethanol atatmospheric pressure to an aminoquinolinone 21 wherein R is alkyl.

The related compounds of the present invention may be prepared from theappropriate precursors by methods essentially the same as thosehereinbeforedescribed.

The 5-amino-5,6,7,8-tetrahydroquinolines and related compounds of thepresent invention are useful as agents for the relief of memorydysfunction, particularly dysfunctions associated with decreasedcholinergic activity such as those found in Alzheimer's disease. Reliefof memory dysfunction activity of the instant compounds is demonstratedin the dark avoidance assay, an assay for the determination of thereversal of the effects of scopolamine induced memory deficitsassociated with decreased levels of acetylcholine in the brain. In thisassay, three groups of 15 male CFW mice were used, a vehicle/vehiclecontrol group, a scopolamine/vehicle group, and a scopolamine/druggroup. Thirty minutes prior to training, the vehicle/vehicle controlgroup received normal saline subcutaneously, and the scopolamine/vehicleand scopolamine/drug groups received scopolamine subcutaneously (3.0mg/kg, administered as scopolamine hydrobromide). Five minutes prior totraining, the vehicle/vehicle control and scopolamine/vehicle groupsreceived distilled water and the scopolamine/drug group received thetest compound in distilled water.

The training/testing apparatus consisted of a plexiglass boxapproximately 48 cm long, 30 cm high and tapering from 26 cm wide at thetop to 3 cm wide at the bottom. The interior of the box was dividedequally by a vertical barrier into a light compartment (illuminated by25-watt reflector lamp suspended 30 cm from the floor) and a darkcompartment (covered). There was a hole at the bottom of the barrier 2.5cm wide and 6 cm tall and a trap door which could be dropped to preventan animal from passing between the two compartments. A CoulbournInstruments small animal shocker was attached to two metal plates whichran the entire length of the apparatus, and a photocell was placed inthe dark compartment 7.5 cm from the vertical barrier and 2 cm off thefloor. The behavioral session was controlled by PDP 11/34 minicomputer.

At the end of the pretreatment interval, an animal was placed in thelight chamber directly under the light fixture, facing away from thedoor to the dark chamber. The apparatus was then covered and the systemactivated. If the mouse passed through the barrier to the darkcompartment and broke the photocell beam within 180 seconds, the trapdoor dropped to block escape to the light compartment and an electricshock was administered at an intensity of 0.4 milliamps for threeseconds. The animal was then immediately removed from the darkcompartment and placed in its home cage. If the animal failed to breakthe photocell beam within 180 seconds, it was discarded. The latency inseconds for each mouse was recorded.

Twenty-four hours later, the animals were again tested in the sameapparatus except that no injections were made and the mice did notreceive a shock. The test day latency in seconds for each animal wasrecorded and the animals were then discarded.

The high degree of variability (due to season of the year, housingconditions, and handling) found in one trial passive avoidance paradigmis well known. To control for this fact, individual cutoff (CO) valueswere determined for each test, compensating for interest variability.Additionally, it was found that 5 to 7% of the mice in thescopolamine/vehicle control groups were insensitive to scopolamine at 3mg/kg, sc. Thus, the CO value was defined as the second highest latencytime in the control group to more accurately reflect the 1/15 expectedcontrol responders in each test group. Experiments with a variety ofstandards repeated under a number of environmental conditions led to thedevelopment of the following empirical criteria: for a valid test, theCO value had to be less than 120 sec and the vehicle/vehicle controlgroup had to have at least 5/15 animals with latencies greater than CO.For a compound to be considered active the scopolamine/compound grouphad to have at least 3/15 mice with latencies greater than CO.

The results of the dark avoidance test are expressed as the number ofanimals per group (%) in which this scopolamine induced memory deficitis blocked as measured by an increase in the latency period. Relief ofmemory dysfunction activity for representative compounds of the presentinvention is presented in the Table.

                  TABLE 1                                                         ______________________________________                                                                   Percent of Animals                                                            with Scopolamine                                                    Dose      Induced Memory                                     Compound         (mg/kg, sc)                                                                             Deficit Reversal                                   ______________________________________                                        N-(1,2,5,6,7,8-hexahydro-                                                                      0.16      20                                                 5-methyl-2-oxo-5-                                                             quinolinyl)acetamide                                                          1-methyl-5-[(2-phenylethyl)-                                                                   1.0       33                                                 amino]-5,6,7,8-tetrahydro-                                                    2(1H)-quinolinone                                                             N-(phenylmethoxy)-N-                                                                           1.0       20                                                 [2-(phenylmethoxy)-5-                                                         5,6,7,8-tetrahydro-                                                           quinolinyl]acetamide                                                          5-[[2-(4-methoxyphenyl)ethyl]-                                                                 0.3       27                                                 amino]-1-methyl-5,6,7,8-tetra-                                                hydro-2(1H)-quinolinone                                                       5-[[2-(3,4-dichlorophenyl)-                                                                    1.0       21                                                 ethyl]amino]-1-methyl-5,6,7,8-                                                tetrahydro-2(1H)-quinolinone                                                  physostigmine    0.31      20                                                 ______________________________________                                    

Relief of memory dysfunction activity is also demonstrated in the invitro inhibition of actylcholinesterase activity, an assay for thedetermination of the ability of a drug to inhibit the inactivation ofacetylcholine, a neurotransmitter implicated in the etiology of memorydysfunction and Alzheimer's dementia. In this assay, a modification of atest described by G. L. Ellman, et al., Biochem. Pharmacol., 7, 88(1961), the following reagents are prepared and employed:

1. 0.05M Phosphate Buffer (pH 7.2)

A solution of monobasic sodium phosphate monhydrate (6.85 g) indistilled water (100 ml) is added to a solution of dibasic sodiumphosphate heptahydrate (13.4 g) and distilled water (100 ml) until a pHof 7.2 was attained. The solution was diluted 1 to 10 with distilledwater.

2. Substrate In Buffer

The 0.05M Phosphate Buffer (pH 7.2) was added to acetylthiocholine (198mg) to a total volume of 100 ml, i.e., a quantity sufficient (gs) to 100ml.

3. 5,5-Dithiobisnitrobenzoic Acid in Buffer

The 0.05M Phosphate Buffer (pH 7.2) was added to5,5-dithiobisnitrobenzoic acid to a total volume of 100 ml, i.e., aquantity sufficient (gs) to 100 ml.

4. Stock Solution of Drug

A 2 millimolar stock solution of the test drug is prepared in a quantitysufficient of a suitable solvent, either acetic acid or dimethylsulfoxide to volume with 5,5-Dithiobisnitrobenzene Acid in Buffer. StockSolution of Drug is serially diluted (1:10) so that the final cuvetteconcentration is 10⁻⁴ molar.

Male Wistar rats are decapitated, brains rapdily removed, corpora stritadissected free, weighed and homogenized in 19 volumes (approximately 7mg protein/ml) of 0.05M phosphate Buffer (pH 7.2) using aPotter-Elvehjem homogenizer. A 25 μaliquot of this suspension is addedto 1 ml of the vehicle or various concentrations of the test drug andpreincubated for 10 minutes at 37° C. Enzyme activity is measured with aBeckman DU-50 spectrophotometer with the following software andinstrument settings:

1. Kinetics Soft-Pac™ Module #598273;

2. Program #6 Kindata;

3. Source--Vis;

4. Wavelength--412 nm;

5. Sipper--none;

6. Cuvettes--2 ml cuvettes using auto 6-sampler;

7. Blank--1 for each substrate concentration;

8. Interval time--15 seconds (15 or 30 seconds for kinetics);

9. Total time--5 minutes (5 or 10 minutes for kinetics);

10. Plot--yes;

11. Span--autoscale;

12. Slope--increasing;

13. Results--yes (gives slope); and

14. Factor--1.

Reagents are added to the blank and sample cuvettes as follows:

    ______________________________________                                        1.   Blank:    0.8 ml 5,5-Dithiobisnitrobenzoic Acid                                         0.8 ml Substrate in Buffer                                     2.   Control:  0.8 ml 5,5-Dithiobisnitrobenzoic Acid/Enzyme                                  0.8 ml Substrate in Buffer                                     3.   Drug:     0.8 ml 5,5-Dithiobisnitrobenzoic Acid/Drug/                                   Enzyme                                                                        0.8 ml Substrate in Buffer                                     ______________________________________                                    

Blank values are determined for each run to control for non-enzymatichydrolysis of substrate and these values are automatically subtracted bythe Kindata program available on kinetics soft-pac module. This programalso calculates the rate of absorbance change for each cuvette.

For IC₅₀ Determinations

Substrate concentration is 10 millimolar diluted 1:2 in assay yieldingfinal concentration of 5 millimolar. 5,5-Dithiobisnitrobenzoic Acidconcentration is 0.5 millimolar yielding 0.25 millimolar finalconcentration. ##EQU1## IC₅₀ values are calculated from log-probitanalysis

                  TABLE II                                                        ______________________________________                                                             Inhibition of                                                                 Acetylcholinesterase                                     Compounds            Activity IC.sub.50 (μM)                               ______________________________________                                        5-[[2-(4-chlorophenyl)ethyl]-                                                                      6.6                                                      amino]-5,6,7,8-tetrahydro-                                                    1-methyl-2(1H)-quinolinone                                                    5,6,7,8-tetrahydo-5- 9.6                                                      [[2-(4-methoxyphenyl)ethyl]amino]-                                            1-methyl-2(1H)-quinolinone                                                    5[[2-(3,4-dichlorophenyl)ethy]-                                                                    2.9                                                      amino]-5,6,7,8-tetrahydro-1-methyl-                                           2(1H)-quinolinone                                                             5,6,7,8-tetrahydro-5-                                                                              3.1                                                      [(2-phenylethyl)amino]-                                                       1-propyl-2(1H)-quinolinone                                                    fumarate                                                                      Physostigmine        0.13                                                     ______________________________________                                    

Memory deficit and scopolamine induced memory deficit reversal isachieved when the present 5-amino-5,6,7,8-tetrahydroquinolines andrelated compounds are administered to a subject requiring such treatmentas an effective oral, parenteral or intravenous dose of from 0.01 to 100mg/kg of body weight per day. A particularly effective amount is about25 mg/kg of body weight per day. It is to be understood, however, thatfor any particular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

Included among the compounds of the present inventions are:

a.5-[[2-(4-hydroxyphenyl)ethyl]amino-1-methyl-5,6,7,8-tetrahydro-2(1H)-quinolinone;

b. N-[2-methoxy-5,6,7,8-tetrahydro-5-quinolinyl]-N-methoxypropionamide;

c.1-(2-phenylethyl)-5-(1-propoxyamino)-5,6,7,8-tetrahydro-2(1H)-quinolinone;

d. 1,5-dimethyl-5-(1-piperidinyl)-5,6,7,8-tetrahydro-2(1H)-quinolinone;

e. 2-hydroxy-5-methyl-5-(1-piperazinyl)-5,6,7,8-tetrahydroquinoline;

f. 1,5-dimethyl-5-(4-morpholinyl)-5,6,7,8-tetrahydro-2(1H)-quinolinone;and

g. 2-hydroxy-5-methyl-5-(4-thiomorpholinyl-5,6,7,8-tetrahydroquinoline.

h.1,5-dimethyl-5-[3-(propynyl)amino]-5,6,7,8-tetrahydro-2(1H)-quinolinone.

i. 5-amino-1,5,6,7-tetrahydro-1,5-dimethyl-2H-1-pyridin-2-one.

Effective amounts of the compounds of the invention may be administeredto a subject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and is some cases intravenously in the form of sterilesolutions. The free base final products, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid, oxalicacid and the like, and salts of tribasic carboxylic acids such as, forexample, carboxysuccinic acid, citric acid and the like.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the aforesaid compoundsmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of present compound in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alignic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotes; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Other dosage unit forms may contain other variousmaterials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 50% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of the activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The following Examples are for illustrative purposes only and are not tobe construed as limiting the invention.

EXAMPLE 1 5,6,7,8-Tetrahydro-5-oxo-2-(phenylmethoxy)quinoline

A suspension of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (33.0 g),silver carbonate (35.0 g), benzyl bromide (44.4 g), and toluene (400 ml)was stirred at room temperature for 72 hrs. The mixture was filtered andthe filtrate was concentrated. Trituration of the residue with petroleumether gave 45.6 g (83%) of product.

EXAMPLE 25,6,7,8-Tetrahydro-5-hydroxy-5-methyl-2-(phenylmethoxy)quinoline

Methylmagnesium bromide (3.0M in diethyl ether, 47 ml) was addeddropwise to a solution of5,6,7,8-tetrahydro-5-2-(phenylmethoxy)quinoline (29.6 g) and toluene (1l) at 0° C. The reaction mixture was allowed to warm to roomtemperature, with stirring. The reaction mixture was then quenched withsaturated ammonium chloride solution, the layers were separated, and theaqueous phase was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated to provide 31.7 g (92.0%) ofproduct.

EXAMPLE 3 5,6,7,8-Tetrahydro-5-methyl-2-(phenylmethoxy)-5-quinolinaminehemifumarate

Trifluoroacetic acid (17.4 g) was added in one portion to a solution of5,6,7,8-tetrahydro-5-methyl-2-(phenylmethoxy)-quinolin-5-ol (41 g),phenylmethoxyamine (47 g), and toluene (770 ml) at room temperature. Thesolution was stirred at room temperature for 24 hrs, and then quenchedwith concentrated ammonium hydroxide solution. The layers were separatedand the aqueous phase was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over potassium carbonate,filtered, and the filtrate was concentrated. Purification by highperformance liquid chromatography (silica gel, elution with ethylacetate-hexanes) gave 44.2 g (77%) of5,6,7,8-tetrahydro-5-methyl-N,2-bis(phenylmethoxy)-5-quinolinamine.

A portion of the5,6,7,8-tetrahydro-5-methyl-N,2-bis(phenylmethoxy)-quinolinamine (30.3g) in tetrahydrofuran (120 ml) was treated dropwise withborane-tetrahydrofuran complex (1M in tetrahydrofuran, 243 ml) at 0° C.The solution was heated under reflux for 2 hrs, cooled to 0° C., andwater (30 ml) was added. The mixture was concentrated in vacuo, 20%potassium hydroxide solution (50 ml) was added, and the mixture washeated under reflux for 1.5 hrs. The mixture was cooled, acidified with6N hydrochloric acid and washed with diethyl ether. The aqueous phasewas basified with potassium hydroxide solution and the mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated.

A 2.9 g-portion of the residue (19.6 g) was dissolved in ethyl acetate,and the solution was treated with an equivalent amount of fumaric acid.The precipitate was collected; yield 2.68 g (68%) of product, mp189°-190° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.19 H.sub.22 N.sub.2 O.sub.3 :                                             69.29% C 6.79% H   8.58% N                                   Found:           69.59% C 6.73% H   8.55% N                                   ______________________________________                                    

EXAMPLE 4 5,6,7,8-Tetrahydro-5-amino-5-methyl-2(1H)-quinolinonehydrochloride

5,6,7,8-Tetrahydro-5-methyl-2-(phenylmethoxy)-5-quinolinaminedihydrochloride (9.5 g) and 10% palladium-on-carbon (730 mg) in absoluteethanol (500 ml) were shaken on a Parr hydrogenation apparatus, startingat 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst wasremoved by filtration, and the filtrate was neutralized with4-polyvinylpyridine and concentrated. The residue was suspended in hotmethanol and the solid was collected. The solid was combined with thematerial that crystallized from the methanol to afford 3.36 g (56%) ofproduct, mp 214°-216° C. (dec).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.10 H.sub.15 N.sub.2 O:                                                    55.94% C 7.04% H  13.05% N                                   Found:           55.71% C 7.02% H  12.91% N                                   ______________________________________                                    

EXAMPLE 5 5,6,7,8-Tetrahydro-5-amino-1,5-dimethyl-2(1H)-quinolinone

A mixture of sodium hydride (50% in oil, 2.9 g),5-amino-5,6,7,8-tetrahydro-5-methyl-2(1H)-quinolinone hydrochloride(5.43 g), and dimethylformamide (370 ml) was stirred at room temperaturefor 1.5 hrs. Methyl iodide (3.97 g) was added, and the mixture was allowto stand at room temperature for 20 hrs. The reaction mixture wasconcentrated in vacuo, and the residue was washed with dichloromethane.The washings were concentrated, the residue was dissolved in a mixtureof ethyl acetate and methanol and treated with 0.5 equivalents offumaric acid. The precipitate (2.65 g) was combined with a 1.9 g-sampleobtained in another experiment, and the combined material was treatedwith 5% sodium hydroxide solution and extracted with dichloromethane.The extract was concentrated. Recrystallization of the residue fromethyl acetate gave 2.1 g (23%) of product, mp 166°-167.5° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.16 N.sub.2 O:                                                    68.72% C 8.39% H  14.57% N                                   Found:           68.68% C 8.37% H  14.52% N                                   ______________________________________                                    

EXAMPLE 6N,2-Bis(phenylmethoxy)-5,6,7,8-tetrahydro-N,5-dimethyl-5-quinolinamine

Methyllithium (1.4M in diethyl ether, 37.7 ml) was added dropwise over20 min to a solution ofN,2-bis(phenylmethoxy)-5,6,7,8-tetrahydro-5-methyl--5-quinolinamine(18.1 g) and tetrahydrofuran (20 ml) at -78° C. The mixture was allowedto warm to room temperature over 2 hrs and was stirred at roomtemperature for an additional 1 hr. The solution was quenched withsaturated ammonium chloride solution and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydrouspotassium carbonate, filtered, and the filtrate was concentrated. Theresidue was purified by high performance liquid chromatography (silicagel, elution with ethyl acetate-hexanes) to provide 12.3 g (65%) ofproduct.

EXAMPLE 75,6,7,8-Tetrahydro-N,5-dimethyl-2-(phenylmethoxy)-5-quinolinamine

5,6,7,8-Tetrahydro-N,5-dimethyl-N,2-bis(phenylmethoxy)-5-quinolinamine(12.3 g) in tetrahydrofuran (160 ml) at 0° C. was treated dropwise withborane-tetrahydrofuran complex (1M in tetrahydrofuran, 63.4 ml). Thesolution was heated under reflux for 3 hrs, cooled to 0° C., and water(30 ml) was added. The reaction mixture was concentrated in vacuo, 20%potassium hydroxide solution (60 ml) was added, and the mixture washeated at reflux for 2 hrs. The mixture was cooled, acidified with conchydrochloric acid, and washed with diethyl ether. The aqueous phase wasbasified with 20% potassium hydroxide solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over potassium carbonate, filtered, and the filtrate wasconcentrated to afford 6.3 g (92%) of product.

EXAMPLE 8 5,6,7,8-Tetrahydro-5-methyl-5-(methylamino)-2(1H)-quinolinonehydrochloride

5,6,7,8-Tetrahydro-N,5-dimethyl-2-(phenylmethoxy)-5-quinolinamine (6.3g) in ethanol (500 ml) was acidified to ca pH2 with a solution ofhydrochloric acid in 2-propanol. 10% Palladium-on-carbon (315 mg) wasadded and the mixture was shaken on Parr hydrogenation apparatus,starting at 55 psi of hydrogen, until hydrogen uptake ceased. Thecatalyst was collected and the filtrate was neutralized with4-polyvinylpyridine. The solution was concentrated in vacuo to a volumeof about 75 ml and diethyl ether was added. The precipitate wascollected and recrystallized first from methanol and then fromwater/2-propanol to afford 1.3 g (25%) of product, mp 190°-195° C.(dec).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.11 H.sub.17 ClN.sub.2 O:                                                  57.77% C 7.49% H  12.25% N                                   Found:           57.36% C 7.46% H  12.11% N                                   ______________________________________                                    

EXAMPLE 95,6,7,8-Tetrahydro-5-hydroxy-2-(phenylmethoxy)-5-(phenylmethyl)quinoline

Benzylmagnesium chloride (1.0M in diethyl ether, 175 ml) was addeddropwise to a solution of5,6,7,8-tetrahydro-5-oxo-2-(phenylmethoxy)quinolinone (37.0 g) and 1.4 lof toluene at 0° C. The mixture was allowed to warm to room temperatureand saturated ammonium chloride solution was added. The layers wereseparated and the aqueous phase was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated toprovide 50.0 g of product.

EXAMPLE 105,6,7,8-Tetrahydro-2-(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine

Trifluoroacetic acid (16.6 g) was added in one portion to a solution of5,6,7,8-tetrahydro-5-hydroxy-2-(phenylmethoxy)-5-(phenylmethyl)quinoline(50 g), phenylmethoxyamine (44.8 g), and toluene (600 ml) at roomtemperature. The solution was stirred at room temperature for 19 hrs,and the reaction mixture was quenched with conc ammonium hydroxidesolution. The layers were separated and the aqueous phase was extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over potassium carbonate, filtered, and the filtrate wasconcentrated. Purification by high performance liquid chromatography(silica gel, elution with ethyl acetate-hexanes) gave 40.0 g (61%) of5,6,7,8-tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine

5,6,7,8-Tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine(40.0 g) in tetrahydrofuran (90 ml) was treated dropwise withborane-tetrahydrofuran complex (1M in tetrahydrofuran, 267 ml) at 0° C.The solution was heated under reflux for 3 hrs, cooled to 0° C. andwater (30 ml) was added. The reaction mixture was concentrated in vacuo,20% potassium hydroxide solution (60 ml) was added, and the mixture washeated under reflux for 8 hours. The mixture was cooled, acidified withconc hydrochloric acid, and washed with diethyl ether. The aqueous phasewas basified with 20% potassium hydroxide solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over potassium carbonate, filtered, and the filtrate wasconcentrated to afford 19.1 g (37.0%) of product.

EXAMPLE 11 5-Amino-5,6,7,8-tetrahydro-5-(phenylmethyl)-2(1H)-quinolinonehydrochloride

A mixture of5,6,7,8-tetrahydro-5-(phenylmethyl)-2-(phenylmethoxy)-5-quinolinamine(19.1 g) and 10% palladium-on-carbon (1.5 g) in ethanol (1 l) wasacidified to about pH 2-3 with 2-propanol/hydrochloric acid solution.The mixture was shaken on Parr hydrogenation apparatus, starting at 55psi of hydrogen, until hydrogen uptake ceased. The catalyst was removedby filtration, the filtrate was neutralized with 4-polyvinylpyridine andconcentrated. The residue was triturated with a mixture of methanol andethyl acetate. The precipitate was collected and recrystallized formwater/methanol/ethyl acetate to afford 4.6 g (28%) of product, mp235°-238° C. (dec), in two crops.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.16 H.sub.19 ClN.sub.2 O:                                                  66.09% C 6.59% H  9.63% N                                    Found:           65.83% C 6.68% H  9.56% N                                    ______________________________________                                    

EXAMPLE 12N-[5,6,7,8-Tetrahydro-5-methyl-2-(phenylmethoxy)-5-quinolinyl]acetamide

Conc sulfuric acid (70 ml) was added dropwise over 45 mins to a solutionof 5,6,7,8-tetrahydro-5-hydroxy-5-methyl-2-(phenylmethoxy)quinoline(14.0 g) and acetonitrile (200 ml) at 0° C. The solution was stirred atroom temperature for 18 hrs, poured over ice, and basified to pH 8 with50% sodium hydroxide solution. The aqueous phase was extracted withethyl acetate, and the combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silicagel, elution with ethyl acetate). The appropriate fractions werecollected and evaporated. Recrystillization (twice) of the residue fromethyl acetate/hexanes gave 2.60 g (16%) of product, mp 153°-154° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.19 H.sub.22 N.sub.2 O.sub.2 :                                             73.52% C 7.14% H  9.02% N                                    Found:           73.88% C 7.12% H  9.02% N                                    ______________________________________                                    

EXAMPLE 13N-(1,2,5,6,7,8-Hexahydro-5-methyl-2-oxo-5-quinolinyl)acetamide

5,6,7,8-Tetrahydro-N-[5-methyl-2-(phenylmethoxy)-5-quinolinyl]acetamidehydrochloride (4.5 g) and 10% palladium-on-carbon (225 mg) in absoluteethanol (250 ml) were shaken on a Parr hydrogenation apparatus at aninitial pressure of 55 psi of hydrogen, until hydrogen uptake ceased.The catalyst was removed by filtration, the filtrate was neutralizedwith 4-polyvinylpyridine, and the mixture was concentrated. The residuewas combined with a 1.79 g sample obtained in another experiment.Recrystallization from absolute ethanol gave 2.81 g (60%) of product, mp235°-237° C. (dec).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.12 H.sub.16 N.sub.2 O.sub.2 :                                             65.43% C 7.32% H  12.72% N                                   Found:           65.02% C 7.27% H  12.54% N                                   ______________________________________                                    

EXAMPLE 14 5,6,7,8-Tetrahydro-5-[(2-phenylethyl)amino]-2(1H)-quinolinonehydrochloride

A mixture of phenethylamine (5.0 g),5,6,7,8-tetrahydro-2-(phenylmethoxy)-5-oxoquinoline (10.0 g), and acatalytic amount of para-toluenesulfonic acid (206 mg) was heated underreflux in toluene (200 ml) with azeotropic removal of water for 36 hrs.The solution was cooled and washed with water. The aqueous phase wasextracted with dichloromethane, and the combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. Sodium borohydride (1.4 g) was added to asolution of the residue and ethyl alcohol (125 ml) and the mixture wasstirred at room temperature for 3 hrs. The reaction mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated to afford 12.5 g (92%) of5,6,7,8-tetrahydro-5-(2-phenethylamino)-2-phenylmethoxy)quinoline.

5,6,7,8-Tetrahydro-5-(2-phenethylamino)-2-(phenylmethoxy)quinoline (12.5g) was converted into its hydrochloride. The hydrochloride and 10%palladium-on-carbon (830 mg) in methanol (1 l) were shaken on a Parrhydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogenuptake ceased. The catalyst was removed by filtration, the filtrate wasneutralized with 4-polyvinylpyridine, and concentrated.Recrystallization of the residue from methanol/ethyl acetate afforded2.68 g of product, mp 200°-202° C. (dec). An additional 2.2 g of productwas obtained from the other liquors; overall yield 42%.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.21 ClN.sub.2 O:                                                  66.99% C 6.94% H  9.19% N                                    Found:           66.85% C 6.96% H  9.12% N                                    ______________________________________                                    

EXAMPLE 155,6,7,8-Tetrahydro-1-methyl-5-[(2-phenylethyl)amino]-2(1H)-quinolinonedihydrochloride monohydrate

A mixture of phenethylamine (6.0 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (8.0 g) and acatalytic amount of para-toluenesulfonic acid was heated in toluene (90ml) under reflux for 18 hrs, with azeotropic removal of water. Thesolution was cooled and washed with water. The aqueous phase wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was washed with hexanes and thesolvent was decanted. Sodium borohydride (0.82 g) was added to asolution of the residue in ethyl alcohol (160 ml) and the mixture wasstirred at room temperature for 0.5 hr. The reaction mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was dissolvedin methanol and treated with ethereal hydrogen chloride. The mixture wasconcentrated in vacuo and the residue was dissolved in ethanol. Ethylacetate was added, the precipitate was collected, and the precipitatewas recrystallized twice from ethanol-ethyl acetate to afford 4.0 (24%)of product, mp 163°-166° C. (softens at 142° C.).

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.18 H.sub.26 Cl.sub.2 N.sub.2 O.sub.2 :                                    57.91% C 7.02% H  7.50% N                                    Found:           57.97% C 6.93% H  7.47% N                                    ______________________________________                                    

EXAMPLE 16 5,6,7,8-Tetrahydro-N,2-bis(phenylmethoxy)-5-quinolinamine

5,6,7,8-Tetrahydro-5-oxo-2-(phenylmethoxy)quinoline (20 g),O-benzylhydroxylamine hydrochloride (19 g), and sodium acetate (9.8 g)in a 1/1-mixture of ethanol and water (200 ml) were heated under refluxfor 3 hrs. The solvent was decanted and the residue was purified by highperformance liquid chromatography (silica gel, elution with 5% ethylacetate/hexanes). The appropriate fractions were collected andevaporated to give 21.5 (76%) of5,6,7,8-tetrahydro-5-oxo-2-(phenylmethoxy)quinoline oxime benzyl ether.

5,6,7,8-Tetrahydro-5-oxo-2-(phenylmethoxy)quinoline oxime benzyl ether(20.3 g) in acetic acid (280 ml) was treated with sodiumcyanoborohydride (14.2 g) at room temperature. After 16 hrs, the mixturewas cooled to 0° C. and acidified with 6N hydrochloric acid. Thereaction mixture was concentrated in vacuo. The residue was dissolved inwater, basified with potassium hydroxide solution, and the mixture wasextracted with dichloromethane. The combined organic layers were driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by high performance liquidchromatography (silica gel, elution with 20% ethyl acetate/hexanes). Theappropriate fractions were collected and evaporated to give 12.0 g (60%)of product.

EXAMPLE 17N-(Phenylmethoxy)-N-[5,6,7,8-tetrahydro-2-(phenylmethoxy)-5-quinolinyl]acetamidehydrochloride

Acetic anhydride (3.77 g) was added to a solution ofN,N-dimethylaminopyridine (0.2 g),N,2-bis(phenylmethoxy)-5,6,7,8-tetrahydro-5-quinolinamine (12.1 g) anddichloromethane (170 ml) at room temperature. The mixture was stirred atroom temperature for 48 hrs, diluted with dichloromethane, and extractedwith saturated sodium bicarbonate solution. The combined extracts werewashed with water, brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was dissolvedin methanol and acidified with 2-propanol/hydrochloric acid solution.The mixture was evaporated and the residue was recrystallized fromethanol/ethyl acetate to give 7.64 g (52%) of product, mp 125°-126° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.25 H.sub.27 ClN.sub.2 O.sub.3 :                                           68.41% C 6.20% H  6.38% N                                    Found:           68.33% C 6.20% H  6.37% N                                    ______________________________________                                    

EXAMPLE 185,6,7,8-Tetrahydro-5-[(2-phenylethyl)amino]-1-(2-propenyl)-2(1H)-quinolinon

A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (20.0 g),lithium hydride (1.57 g), and dimethylformamide (800 ml) was stirred for3 hrs at 25° C., under nitrogen. 3-Bromopropene (15.5 g) was added andthe mixture was stirred for an additional eighteen hrs. The reactionmixture was concentrated and the residue was partitioned between ethylacetate and water. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine, dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated. The residue was triturated withpetroleum ether to afford 15.7 g (63%) of5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone.

A mixture of phenethylamine (6.1 g),5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone (10.0 g), anda catalytic amount of para-toluenesulfonic acid was heated in refluxingtoluene (150 ml), with azeotropic removal of water, for 18 hrs. Thesolution was cooled and washed with water. The aqueous phase wasextracted with dichloromethane, and the combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. Sodium borohydride (1.8 g) was added tothe residue in ethyl alcohol (150 ml) and the resulting mixture wasstirred at room temperature for 0.5 hr. The mixture was concentrated invacuo, and the residue was quenched with water. The mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by high performanceliquid chromatography (silica gel, eluted with methanol/ethyl acetate)to afford 13.6 g (89%) of product. Recrystallization from diethylether/petroleum ether provided the analytical sample, mp 60°-62° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.20 H.sub.24 N.sub.2 O:                                                    77.89% C 7.84% H  9.08% N                                    Found:           78.06% C 7.65% H  9.10% N                                    ______________________________________                                    

EXAMPLE 195-[[2-(3,4-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-(2-propenyl)-2(1H)-quinolinonefumarate

A mixture of 2-(3,4-dichlorophenyl)ethylamine (3.8 g),5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (225 mg) was heated in refluxing toluene (50ml), with azeotropic removal water, for 24 hrs. An additional 1 g of theamine was added, and the mixture was heated for an additional 24 hrs.The solution was cooled, and the mixture was concentrated in vacuo.Sodium borohydride (0.56 g) was added to a solution of the residue inethyl alcohol (50 ml), and the resulting mixture was stirred at roomtemperature for 1 hr. The mixture was concentrated in vacuo, and theresidue was quenched with water. The mixture was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by high performance liquidchromatography (silica gel, eluted with 5% methanol/ethyl acetate) toprovide 4.03 g (73%) of basic product. The product was dissolved inethanol, treated with an equivalent amount of fumaric acid, and themixture was concentrated in vacuo. The residue was recrystallized fromethanol to provide the analytical sample, mp 160°-161° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.26 Cl.sub.2 N.sub.2 O.sub.5 :                                    58.43% C 5.31% H  5.68% N                                    Found:           58.41% C 5.61% H  5.67% N                                    ______________________________________                                    

EXAMPLE 205,6,7,8-Tetrahydro-5-[(2-phenylethyl)amino]-1-propyl-2(1H)-quinolinonefumarate

A mixture of5,6,7,8-tetrahydro-5-[(2-phenylethyl)amino]-(2-propenyl)-2(1H)-quinolinone(4.68 g) and 10% palladium-on-carbon (0.47 g) in ethanol (100 ml) wasstirred under hydrogen at atmospheric pressure for 3 hrs. The mixturewas filtered through celite, and the filtrate was concentrated. Theresidue solidified upon standing. The solid was dissolved in ethanol andtreated with an equivalent amount of fumaric acid. The mixture wasevaporated, and the residue was recrystallized twice, first fromethanol/ethyl acetate, and then from ethanol to provide 4.63 g (71%) ofproduct, mp 151°-153° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.30 N.sub.2 O.sub.5 :                                             67.59% C 7.09% H  6.57% N                                    Found:           67.61% C 7.09% H  6.59% N                                    ______________________________________                                    

EXAMPLE 215-[[2-(3,4-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-(phenylmethyl)-2(1H)-quinolinonefumarate

A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (5.0 g), lithiumhydride (0.37 g), and dimethylformamide (200 ml) was stirred at 25° C.for 3 hrs. Benzyl bromide (5.5 g) was added and the mixture was stirredfor 20 hrs. Water was added, and the mixture was concentrated underreduced pressure. The residue was partitioned between ethyl acetate andwater. The layers were separated and combined organic phase was washedwith water, brine, dried over anhydrous magnesium sulfate, filtered, andthe filtrate was concentrated. The residue was triturated with hexanesto provide 4.5 (58%) of5,6,7,8-tetrahydro-5-oxo-1-phenylmethyl-2(1H)-quinolinone.

A mixture of 2-(3,4-dichlorophenyl)ethylamine (2.7 g),5,6,7,8-tetrahydro-5-oxo-1-phenylmethyl-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (180 mg) was heated in 50 ml of refluxingtoluene, with azeotropic removal of water, for 25 hrs. An additional 1 gof the amine was added, and the mixture was heated for an additional 63hrs. The solution was cooled and concentrated in vacuo. Sodiumborohydride (0.45 g) was added to a solution of the residue in ethylalcohol (50 ml), and the mixture was stirred at room temperature for 1hr. The mixture was concentrated in vacuo, the residue was quenched withwater, and the product was extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by high performance liquid chromatography (silica gel, elutedwith methanol/ethyl acetate) to afford 4.0 g (80%) of basic product. Thebasic product was dissolved in hot ethanol and treated with anequivalent amount of fumaric acid. The solvent was removed and theresidue was recrystallized from ethanol/ethyl acetate to provide 3.0 gof the analytical sample, mp 176°-178° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.28 H.sub.28 Cl.sub.2 N.sub.2 O.sub.5 :                                    61.88% C 5.19% H  5.15% N                                    Found:           61.59% C 5.16% H  5.07% N                                    ______________________________________                                    

EXAMPLE 225,6,7,8-Tetrahydro-1-methyl-5-[(phenylmethyl)amino]-2(1H)-quinolinonefumarate

A mixture of benzylamine (2.2 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (0.13 g) was heated in refluxing toluene (50ml), with azeotropic removal of water, for 40 hrs. An additional 0.98 gof amine and 0.1 g of para-toluenesulfonic acid were added. The reactionmixture was heated under reflux for an additional 24 hrs, and thencooled. The mixture was concentrated in vacuo. Sodium borohydride (0.6g) was added to a solution of the residue in ethyl alcohol (50 ml), andthe mixture was stirred at room temperature for 1 hr. The mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was purified byhigh performance liquid chromatography (silica gel, eluted withmethanol/ethyl acetate) to give 3.1 g (69%) of basic product. The basicproduct was dissolved in ethanol and treated with 1.34 g of fumaric acidto give the fumarate, mp 159°-161° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.21 H.sub.24 N.sub.2 O.sub.5 :                                             65.61% C 6.29% H  7.29% N                                    Found            65.23% C 6.32% H  7.11% N                                    ______________________________________                                    

EXAMPLE 235-[[2-(4-Trifluoromethylphenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-methyl-2(1H)-quinolinone

A mixture of 2-(4-trifluoromethylphenyl)ethylamine (4.1 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (256 mg) was heated in refluxing toluene (50ml), with azeotropic removal or water, for 40 hrs. An additional 2.0 gof the amine was added and the mixture was refluxed for 36 hr. Thesolution was cooled, and the mixture was concentrated in vacuo. Sodiumborohydride (0.6 g) was added to a solution of the residue in ethylalcohol (50 ml), and the resulting mixture was stirred at roomtemperature for 1 hr. The mixture was concentrated in vacuo, the residuewas quenched with water, and the mixture was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was recrystallized from ethyl acetate/hexanesto provide, in two crops, 3.8 g (65%) of product, mp 104°-106° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.19 H.sub.21 F.sub.3 N.sub.2 O:                                            65.13% C 6.04% H  7.99% N                                    Found:           65.13% C 6.16% H  7.97% N                                    ______________________________________                                    

EXAMPLE 245,6,7,8-Tetrahydro-1-methyl-5-[[2-(4-nitrophenyl)ethyl]amino]-2(1H)-quinolinone

A mixture of 2-(4-nitrophenyl)ethylamine (3.4 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (256 mg) was heated in refluxing toluene (70ml), with azeotropic removal of water, for a total of 72 hrs. Anadditional 1.0 g of the amine was added at 24 and 48 hrs. The resultingsolution was cooled and concentrated in vacuo. Sodium borohydride (0.6g) was added to a solution of the residue in ethyl alcohol (70 ml). Theresulting mixture was stirred at room temperature for 1 hr, and themixture was concentrated in vacuo. The residue was quenched with water,and the mixture was extracted with dichloromethane. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate concentrated. The residue was purified byhigh performance liquid chromatography (silica gel, eluted withmethanol/ethyl acetate) to provide 3.8 g (69%) of product.Recrystallization from ethyl acetate afforded the analytical sample, mp138°-139° C.,

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.18 H.sub.21 N.sub.3 O.sub.3 :                                             66.04% C 6.47% H  12.84% N                                   Found:           65.82% C 6.19% H  12.66% N                                   ______________________________________                                    

EXAMPLE 255-[[2-(4-Chlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-methyl-2(1H)-quinolinone

A mixture of 2-(4-chlorophenyl)ethylamine (5.8 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (5.5 g), and acatalytic amount of para-toluenesulfonic acid was heated in refluxingtoluene (90 ml), with azeotropic removal of water, for 40 hrs. Thesolution was cooled and concentrated in vacuo. Sodium borohydride (1.1g) was added to a solution of the residue in ethyl alcohol (90 ml), andthe mixture was stirred at room temperature for 2 hrs. The mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. Recrystallization of theresidue from ethyl acetate/hexanes provided 6.55 g (67%) of product, mp110°-112° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.18 H.sub.21 N.sub.2 O:                                                    68.24% C 6.68% H  8.84% N                                    Found:           68.36% C 6.74% H  8.78% N                                    ______________________________________                                    

EXAMPLE 265,6,7,8-Tetrahydro-5-[[2-(4-methoxyphenyl)ethyl]amino]-1-methyl-2(1H)-quinolinone

A mixture of 2-(4-methoxyphenyl)ethylamine (5.6 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (5.5 g), and acatalytic amount of para-toluenesulfonic acid was heated in refluxingtoluene (90 ml), with azeotropic removal of water, for 39 hrs. Thesolution was cooled and concentrated in vacuo. Sodium borohydride (1.1g) was added to a solution of the residue in ethyl alcohol (90 ml), andthe mixture was stirred at room temperature for 2 hrs. The mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. The residue was washed withdiethyl ether to afford 7.8 g (81%) of product. Recrystallization fromethyl acetate/hexanes provided the analytical sample, mp 97°-99° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.19 H.sub.24 N.sub.2 O.sub.2 :                                             73.05% C 7.74% H  8.97% N                                    Found:           73.38% C 7.48% H  9.01% N                                    ______________________________________                                    

EXAMPLE 275,6,7,8-Tetrahydro-1-methyl-5-[[2-(4-methylphenyl)ethyl]amino]-2(1H)-quinolinonefumarate

A mixture of 2-(4-methylphenyl)ethylamine (2.7 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (0.13 g) was heated in refluxing toluene (50ml), with azeotropic removal of water, for 42 hrs. The mixture wascooled and concentrated in vacuo. Sodium borohydride (0.64 g) was addedto a solution of the residue in 50 ml of ethyl alcohol, and the mixturewas stirred at room temperature for 1 hr. The mixture was concentratedin vacuo, the residue was quenched with water, and the mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was dissolved in ethanol, treatedwith 1.9 g of fumaric acid, and the salt was allowed to crystallize.Recrystallization from ethanol/2-isopropyl ether gave 3.87 g (56%) ofproduct, mp 158°-161° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.23 H.sub.28 N.sub.2 O.sub.5 :                                             66.97% C 6.84% H  6.79% N                                    Found:           67.05% C 6.88% H  6.78% N                                    ______________________________________                                    

EXAMPLE 285-[[2-(2,4-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-methyl-2(1H)-quinolinone

A mixture of 2-(2,4-dichlorophenyl)ethylamine (3.8 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (256 mg) was heated in refluxing toluene (50ml), with azeotropic removal of water, for 40 hrs. An additional 2.0 gof the amine was added and the mixture was refluxed for 36 hrs. Thesolution was cooled and concentrated in vacuo. Sodium borohydride (0.6g) was added to a solution of the residue in 50 ml of ethyl alcohol, andthe mixture was stirred at room temperature for 1 hr. The mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. Recrystallization of theresidue from ethyl acetate/hexanes provided 2.5 g (42%) of product, mp102°-103° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.18 H.sub.20 Cl.sub.2 N.sub.2 O:                                           61.55% C 5.74% H  7.97% N                                    Found:           61.66% C 5.86% H  8.03% N                                    ______________________________________                                    

EXAMPLE 295-[[2-(3,4-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-methyl-2(1H)-quinolinone

A mixture of 2-(3,4-dichlorophenyl)ethylamine (3.8 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (130 mg) was heated in refluxing toluene (50ml), with azeotropic removal of water, for 41 hrs. An additional 1 g ofthe amine and 0.1 g of para-toluenesulfonic acid were added, and themixture was heated for an additional 24 hrs. The solution was cooled andthe precipitate was collected. Sodium borohydride (0.6 g) was added to asolution of the precipitate in ethyl alcohol (50 ml), and the mixturewas stirred at room temperature for 1 hr. The mixture was concentratedin vacuo, the residue was quenched with water, and the mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was dissolved in hot ethanol andtreated with an equivalent amount of fumaric acid. The solid wascollected and recrystallized from ethanol to provide 3.8 g (48%) ofproduct, mp 172°-173° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.22 H.sub.24 Cl.sub.2 N.sub.2 O.sub.5 :                                    56.54% C 5.18% H  5.99% N                                    Found:           56.45% C 5.04% H  5.91% N                                    ______________________________________                                    

EXAMPLE 305,6,7,8-Tetrahydro-1-methyl-5-[[2-(2,2-diphenyl)ethyl]amino]-2(1H)-quinolinone

A mixture of 2,2-diphenylethylamine (4.3 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (256 mg) was heated in 70 ml of refluxingtoluene, with azeotropic removal of water, for 24 hrs. An additional 2.0g of the amine was added, and the mixture was refluxed for 24 hrs. Thesolution was cooled and concentrated in vacuo. Sodium borohydride (0.6g) was added to a solution of the residue in ethyl alcohol (70 ml), andthe mixture was stirred at room temperature for 1 hr. The mixture wasconcentrated in vacuo, the residue was quenched with water, and themixture was extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated. Recrystallization of theresidue from ethyl acetate/hexanes provided 3.4 g (57%) of product, mp110°-112° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.26 N.sub.2 O:                                                    80.41% C 7.31% H  7.81% N                                    Found:           80.42% C 7.44% H  7.63% N                                    ______________________________________                                    

EXAMPLE 315,6,7,8-Tetrahydro-1-methyl-5-[(3-phenylpropyl)amino]-2(1H)-quinolinonefumarate

A mixture of 3-phenylpropylamine (2.7 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (130 mg) was heated in refluxing toluene (50ml), with azeotropic removal of water, for 24 hrs. An additional 1 g ofthe amine and 0.1 of para-toluenesulfonic acid were added, and themixture was heated for an additional 18 hrs. The solution was cooled andconcentrated in vacuo. Sodium borohydride (0.6 g) was added to asolution of the residue in ethyl alcohol (50 ml), and the mixture wasstirred at room temperature for 1 hr. The mixture was concentrated invacuo, the residue was quenched with water, and the mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was washed with hexanes,dissolved in hot ethanol, and treated with an equivalent amount offumaric acid to provide 5.5 g (80%) of product. Recrystallization fromethanol gave the analytical sample, mp 171°-173° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.23 H.sub.28 N.sub.2 O.sub.5 :                                             66.97% C 6.84% H  6.79% N                                    Found:           66.77% C 6.78% H  6.78% N                                    ______________________________________                                    

EXAMPLE 325-[[2-(4-Chlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1,7,7-trimethyl-2(1H)quinolinonefumarate

A mixture of 5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-2(1H)-quinolinone(15.0 g), methyl iodide (12.3 g), potassium carbonate (21.6 g), anddimethylformamide (230 ml) was stirred at room temperature for 21 hrs.The reaction mixture was filtered, and the filtrate was concentrated.Ethyl acetate was added to the residue, and the mixture was filtered.The filtrate was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and the filtrate was concentrated to give 8.1 g (50%)of 5,6,7,8-tetrahydro-5-oxo-1,7,7-trimethyl-2(1H)-quinolinone.

A mixture of 5,6,7,8-tetrahydro-2-(4-chlorophenyl)ethylamine (3.6 g),1,7,7-trimethyl-5-oxo-2(1H)-quinolinone (4.0 g), andpara-toluenesulfonic acid (0.11 g) was heated in refluxing toluene (60ml), with azeotropic removal of water, for 48 hrs, at which time anadditional 3.6 g of amine and 0.1 g of para-toluenesulfonic acid wereadded. The mixture was refluxed for a total of 72 hrs. The mixture wascooled and concentrated in vacuo. Sodium borohydride (1.0 g) was addedto a solution of the residue in ethyl alcohol (50 ml), and the mixturewas stirred at room temperature for 1 hr. The mixture was concentratedin vacuo, the residue was quenched with water, and the mixture wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by high performanceliquid chromatography (silica gel, eluted with methanol/ethyl acetate).The appropriate fractions were collected and evaporated. The residue wasdissolved in methanol and treated with 0.74 g of fumaric acid. Themixture was evaporated, and the residue triturated with ethyl acetate togive 2.8 g (31%) of product. Recrystallization from ethanol give theanalytical sample, mp 155°-156° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.29 ClN.sub.2 O.sub.5 :                                           62.54% C 6.34% H  6.08% N                                    Found:           62.32% C 6.21% H  6.43% N                                    ______________________________________                                    

EXAMPLE 335-[[2-(3,4,-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-propyl-2(1H)-quinolinone

A mixture of 2-(3,4-dichlorphenyl)ethylamine (4.2 g)5,6,7,8-tetrahydro-1-propyl-5-oxo-2(1H)-quinolinone (3.5 g), andpara-toluenesulfonic acid (257 mg) was heated in refluxing toluene (70ml), with azeotropic removal of water, for 40 hrs. An additional 1 g ofthe amine was added after 40 and 64 hrs. The mixture was heated for atotal of 88 hrs. The solution was cooled and evaporated in vacuo.

Sodium borohydride (0.60 g) was added to a solution of the residue inethyl alcohol (70 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was evaporated in vacuo. The residue was quenchedwith water, and the mixture was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was purified by high performance liquid chromatography on silicagel (elution with methanol/ethyl acetate to afford 4.8 g (75%) ofproduct. Recrystallization from ethyl acetate/hexanes provided theanalytical sample, mp 105°-107° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.20 H.sub.24 Cl.sub.2 N.sub.2 O:                                           63.33% C 6.38% H  7.38% N                                    Found:           63.10% C 6.22% H  7.36% N                                    ______________________________________                                    

EXAMPLE 345,6,7,8-Tetrahydro-1-methyl-5-[[2-(1-napthyl)ethyl]amino]-2(1H)-quinolinonefumarate

A mixture of 2-(1-naphthyl)ethylamine (3.7 g),5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), andpara-toluenesulfonic acid (256 mg) was heated in refluxing toluene (70ml), with azeotropic removal of water, for 24 hrs. An additional 2 g ofthe amine was added, and the mixture was heated for an additional 24hrs. The solution was cooled and evaporated in vacuo.

Sodium borohydride (0.60 g) was added to a solution of the residue inethyl alcohol (70 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was evaporated in vacuo, the residue was quenchedwith water, and the mixture was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate concentrated. The residuewas purified by high performance liquid chromatography on silica gel(elution with methanol/ethyl acetate) to afford 4.59 g (82%) of product.The product was dissolved in methanol and treated with an equivalentamount of fumaric acid. The solution was evaporated in vacuo, and theresidue was recrystallized from methanol. The solid was stirred in hotmethanol, and the mixture was filtered to provide the analytical sample,mp 189°-191° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.26 H.sub.28 N.sub.2 O.sub.5 :                                             69.33% C 6.29% H  6.25% N                                    Found:           69.38% C 6.39% H  6.21% N                                    ______________________________________                                    

EXAMPLE 355-[[2-(4-Chlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-(2-propenyl)-2(1H)-quinolinonehydrochloride

A mixture of 2-(4-chlorophenyl)ethylamine (5.5 g),5,6,7,8-tetrahydro-5-oxo-(2-propenyl)-2(1H)-quinolinone (6.0 g), andpara-toluenesulfonic acid (450 mg) was heated in refluxing toluene (100ml), with azeotropic removal of water, for 24 hrs. An additional 2 g ofthe amine was added, and the mixture was heated for an additional 48hrs. The solution was cooled and evaporated in vacuo.

Sodium borohydride (1.12 g) was added to a solution of the residue inethyl alcohol (100 ml), and the resulting mixture was stirred at roomtemperature for 1 hr. The mixture was evaporated in vacuo, the residuewas quenched with water, and the mixture was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by high performance liquidchromatography on silica gel (elution with 5% methanol/ethyl acetate toprovide 8.50 g (85%) of product. A portion of product was dissolved inmethanol and treated with etheral hydrogen chloride. The mixture wasevaporated in vacuo, and the residue was crystallized frommethanol/isopropyl ether to provide the analytical sample, mp 175°-177°C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.20 H.sub.24 Cl.sub.2 N.sub.2 O:                                           63.33% C 6.38% H  7.38% N                                    Found:           63.00% C 6.53% H  7.03% N                                    ______________________________________                                    

EXAMPLE 365-[[2-(4-Chlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-propyl-2(1H)-quinolinonefumarate

A mixture of5-[[2-(4-chlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-(2-propenyl)-2(1H)-quinolinone(4.5 g) and 10% palladium-on-carbon (0.45 mg) in ethanol (100 ml) wasstirred under an atmosphere of hydrogen for 3 hrs. The mixture wasfiltered through celite, and the filtrate was concentrated. The residuewas filtered through silica gel (elution with ethyl acetate/methanol),and the filtrate was evaporated. The residue was dissolved in ethanol,treated with an equivalent amount of fumaric acid, and the salt wasallowed to crystallize. The precipitate was collected to provide 3.0 g(50%) of product, mp 166°-168° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.24 H.sub.29 ClN.sub.2 O.sub.5 :                                           62.54% C 6.34% H  6.08% N                                    Found:           62.73% C 6.19% H  6.05% N                                    ______________________________________                                    

EXAMPLE 375-[[2-(3,4-Dichlorophenyl)ethyl]amino]-1-hexyl-5,6,7,8-tetrahydro-2(1H)-quinolinonefumarate

A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (10.0 g),lithium hydride (0.78 g), and dimethylformamide (400 ml) was stirred for3 hrs at 25° C., under nitrogen. 1-Bromohexane (10.6 g) was added andthe mxture was stirred for an additional eighteen hrs. The reactionmixture was concentrated and the residue was partitioned between ethylacetate and water. The layers were separted and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine, dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated. The residue was purified by highperformance liquid chromatography (silica gel, two columns, eluted with50% ethyl acetate/hexane). The appropriate fractions were collected andevaporated to give 4.6 (31%) of1-hexyl-5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone.

Titanium tetra-isopropoxide (11.6 g) was rapidly added dropwise to asuspension of 1-hexyl-5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (4.6 g)and 3,4-dichlorophenethylamine (7.0 g) in acetonitrile (38 ml). Themixture was stirred at room temperature for 20 hrs and water anddichloromethane were added. The layers were separated, and the aqueousphase was extracted with dichloromethane. The combined organic phaseswere filtered, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was concentrated.

Sodium borohydride (706 mg) was added to a solution of the residue inethyl alcohol (80 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was evaporated in vacuo, the residue was quenchedwith water, and the mixture was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was purified by high performance liquid chromatography on silcagel (elution with 5% methanol/ethyl acetate) to provide 5.8 g (74%) ofproduct. The product was dissolved in ethanol and treated with anequivalent amount of fumaric acid. The mixture was concentrated invacuo, ethyl acetate was added, and the product was allowed tocrystallize to provide the analytical sample, mp 160°-162° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.27 H.sub.34 Cl.sub.2 N.sub.2 O.sub.5 :                                    60.34% C 6.38% H  5.21% N                                    Found:           60.01% C 6.26% H  5.05% N                                    ______________________________________                                    

EXAMPLE 385-[[2-(3,4-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-(3-methyl-2-butenyl)-2(1H)-quinolinonemaleate

A mixture of 5,6,7,8-tetrahydro-5-oxo-(2(1H)-quinolinone (10.0 g),lithium hydride (0.79 g), and dimethylformamdie (400 ml) was stirred for3 hrs at 25° C., under nitrogen. 3-Methybutenyl bromide (10.6) was addedand the mixture was stirred for an additional eighteen hrs. The reactionmixture was concentrated and the residue was partitioned between ethylacetate and water. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine, dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated. The residue was triturated withpetroleum ether to afford 10.5 g (74%) of5,6,7,8-tetrahydro-1-(3-methyl-2-buteneyl)-5-oxo-2(1H)-quinolinone.

A mixture of 3,4-dichlorophenethylamine (7.9 g),5,6,7,8-tetrahydro-1-(3-methyl-2-butenyl)-5-oxo-2(1H)-quinolinone (8.0g), and para-toluenesulfonic acid (526 mg) was heated in refluxingtoluene (100 ml), with azeotropic removal of water, for 18 hrs. Anadditional 2 g of the amine was added, and the mixture was heated for anadditional 68 hrs. The solution was cooled and evaporated in vacuo.

Sodium borohydride (1.3 g) was added to a solution of the residue inethyl alcohol (100 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was evaporated in vacuo, the residue was quenchedwith water, and the mixture was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was purified by high performance liquid chromatography on silicagel (elution with methanol/ethyl acetate) to afford 11.5 g (82%) ofproduct as an oil. The product was dissolved in hot ethanol and treatedwith an equivalent amount of maleic acid. The solution was allowed tocool, the precipitate was collected to provide the analytical sample, mp103°-107° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.26 H.sub.30 Cl.sub.2 N.sub.2 O.sub.5 :                                    59.89% C 5.80% H  5.37% N                                    Found:           59.35% C 5.51% H  5.32% N                                    ______________________________________                                    

EXAMPLE 395,6,7,8-Tetrahydro-1-methyl-5-[[2-(2-napthyl)ethyl]amino]-2(1H)-quinolinone

Titanium tetra-isopropoxide (10.5 g) was rapidly added to a solution of5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g) and2-(2-napthyl)ethylamine (5.8 g) in acetonitrile (35 ml). The mixture wasstirred at room temperature for 20 hrs and dichloromethane and waterwere added. The mixture was filtered, the layers of the filtrate wereseparated, and the aqueous phase was extracted with dichloromethane. Thecombined organic phases were dried over anhydrous magnesium sulfate,filtered, and the filtrate was concentrated.

Sodium borohydride (600 mg) was added to a solution of the residue inethyl alcohol (100 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was concentrated in vacuo, the residue wasquenched with water, and the mixture was extracted with dichloromethane.The combined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated. Theresidue was recrystallized twice from ethyl acetate to provide 2.5 g(45%) of product, mp 113°-115° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.22 H.sub.24 N.sub.2 O:                                                    79.48% C 7.28% H  8.43% N                                    Found:           79.66% C 7.43% H  8.48% N                                    ______________________________________                                    

EXAMPLE 405-[[2-(3,4-Dichlorophenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-(2-phenylethyl)-2(1H)-quinolinone

A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (7.5 g), lithiumhydride (0.59 g), and dimethylformamide (300 ml) was stirred for 3 hrsat 25° C., under nitrogen. 2-Phenylethyl bromide (9.36 g) was added andthe mixture was stirred for an additional eighteen hrs. The reactionmixture was concentrated and the residue was partitioned between ethylacetate and water. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith water and brine, dried over anhydrous magnesium sulfate, filtered,and the filtrate was concentrated. The residue was triturated withpetroleum ether to afford 3.0 g (24%) of5,6,7,8-tetrahydro-5-oxo-1-(2-phenylethyl)-2(1H)-quinolinone.

Titanium tetra-isopropoxide (7.0 g) was rapidly added to a solution of5,6,7,8-tetrahydro-5-oxo-1-(2-phenylethyl)-2(1H)-quinolinone (3.0 g),and 2-(3,4-dichlorophenyl)ethylamine (5.8 g) in acetonitrile (25 ml).The mixture was stirred at room temperature for 20 hrs anddichloromethane and water were added. The mixture was filtered, thelayers of the filtrate were separated, and the aqueous phase wasextracted with dichloromethane. The combined organic phases were driedover anhydrous magnesium sulfate, filtered, and the filtrate wasconcentrated.

Sodium borohydride (420 mg) was added to a solution of the residue inethyl alcohol (50 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was concentrated in vacuo, the residue wasquenched with water, and the mixture was extracted with dichloromethane.The combined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated.Recrystallization of the residue from ethyl acetate/hexanes provided 2.6g (52%) of product, mp 120°-122° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.25 H.sub.26 Cl.sub.2 N.sub.2 O:                                           68.03% C 5.94% H  6.35% N                                    Found:           68.01% C 5.81% H  6.27% N                                    ______________________________________                                    

EXAMPLE 415-[[2-(1-Cyclohexenyl)ethyl]amino]-5,6,7,8-tetrahydro-1-methyl-2(1H)-quinolinone

Titanium tetra-isopropoxide (21.0 g) was rapidly added to a solution of5,6,7,8-tetrahydro-5-oxo-1-methyl)-2(1H)-quinolinone (6.0 g) and2-(1-cyclohexenyl)ethylamine (8.4 g) in acetonitrile (70 ml). Themixture was stirred at room temperature for 20 hrs and dichloromethaneand water were added. The mixture was filtered, the layers of thefiltrate were separated, and the aqueous phase was extracted withdichloromethane. The combined organic phases were dried over anhydrousmagnesium sulfate, filtered, and the filtrate was concentrated.

Sodium borohydride (1.2 mg) was added to a solution of the residue inethyl alcohol (150 ml), and the mixture was stirred at room temperaturefor 1 hr. The mixture was concentrated in vacuo, the residue wascarefully quenched with water, and the mixture was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous magnesium sulfate, filtered, and the filtrateconcentrated. Recrystallization or the residue from ethylacetate/hexanes provided 3.5 g (32%) of product, mp 184°-187° C.

    ______________________________________                                        ANALYSIS:                                                                     ______________________________________                                        Calculated for C.sub.18 H.sub.26 N.sub.2 O:                                                    75.48% C 9.15% H  9.78% N                                    Found:           75.69% C 9.32% H  9.79% N                                    ______________________________________                                         ##STR19##

We claim:
 1. A process for the preparation of a compound of theformulawherein R is hydrogen, loweralkyl, loweralkenyl, loweralkynyl, orarylloweralkyl; R² is hydrogen, loweralkyl, arylloweralkyl,diaryloweralkyl, lowercycloalkenylloweralkyl, loweralkoxy, orarylloweralkoxy; R⁵ is hydrogen, loweralkyl, or arylloweralkyl; m is 0,1, or 2; and n is 1 or 2; which comprises (a) contacting a compound ofthe formula ##STR20## wherein R, R⁵, m and n are as above with acompound of the formula

    R.sup.2 NH.sub.2

wherein R² is as above in the presence of titanium tetra-isopropoxide toprovide an imine of the formula ##STR21## wherein R, R², R⁵, and m areas above, and (b) contacting the imine with an alkali metal borohydride.2. The process of claim 1 wherein a solvent is employed in step (a). 3.The process of claim 2 wherein the solvent is acetonitrile.
 4. Theprocess of claim 1 wherein the alkali metal borohydride is sodiumborohydride.